Although BCL2 has long been implicated in therapy resistance across cancers, its role in early-stage CSPC had not been fully defined. Using a combination of patient-derived datasets, in vitro models, and in vivo systems, we demonstrated that androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) universally induce BCL2 expression in CSPC, even in the absence of specific genomic alterations.
Notably, this BCL2 upregulation occurs alongside a suppression of androgen receptor (AR) activity, suggesting an inverse regulatory relationship. This dynamic is illustrated in Figure 1, which summarizes the reciprocal crosstalk between AR, BCL2, and PI3K/AKT pathways and the therapeutic effect of BCL2 inhibition in delaying resistance. This work addresses a highly relevant clinical problem: over 90% of men with advanced prostate cancer initially respond to ADT, but most will eventually progress to CRPC within 2–3 years, at which point the disease becomes incurable.2,3 CRPC accounts for the majority of the over 35,000 prostate cancer-related deaths each year in the United States alone. If BCL2 inhibition in combination with ADT and ARSIs proves effective in delaying or preventing this transition, the impact could be substantial—potentially extending the duration of castration sensitivity and improving survival for thousands of men annually, particularly those with high-risk localized or metastatic CSPC.
Figure 1: Androgen deprivation therapy (ADT) induces BCL2 expression in castration-sensitive prostate cancer (CSPC), which activates reciprocal crosstalk between the androgen receptor (AR) and PI3K/AKT signaling pathways. This non-canonical signaling loop drives early castration resistance. BCL2 inhibition with venetoclax disrupts this feedback and delays the progression to castration-resistant prostate cancer (CRPC). Adapted from Hirani et al., Cell Reports 2025(1).
Beyond confirming the association between BCL2 and ADT resistance, we uncovered a non-canonical feedback loop between the AR, BCL2, and PI3K/AKT pathways. This triad forms a reciprocal crosstalk that sustains tumor survival and enables escape from AR-targeted therapy. Interestingly, we found that BCL2 overexpression alone is sufficient to drive resistance to AR signaling inhibitors (ARSIs) like enzalutamide and rewire oncogenic transcriptional networks, including metabolic and survival pathways.
To assess therapeutic relevance, we evaluated venetoclax, a selective BCL2 inhibitor already approved by the FDA for hematologic malignancies. Our data show that venetoclax delays the emergence of CRPC when combined with ARSI in both cell lines and mouse models. Importantly, the drug’s effect was significantly enhanced when paired with ARSI therapy, suggesting a rationale for combination regimens in early-stage CSPC.
However, timing is critical. We observed that BCL2 inhibition is less effective in established CRPC, likely due to the emergence of compensatory pathways and lineage plasticity. Indeed, prolonged ADT in BCL2-overexpressing CSPC cells induced epithelial-to-mesenchymal transition (EMT) and activation of Hedgehog signaling, markers of aggressive disease and treatment resistance.4 This reinforces the need for early intervention before molecular plasticity sets in.
Taken together, our findings redefine BCL2 not just as a survival protein but as an active molecular driver of early castration resistance. We propose that BCL2-targeted strategies be explored in the neoadjuvant or mCSPC setting, rather than waiting until resistance has already emerged. Our work provides a scientific foundation to support clinical trials evaluating venetoclax or next-generation BCL2 inhibitors in combination with ADT and ARSIs, particularly in patients with high BCL2 expression or PTEN loss. By integrating molecular insight with translational potential, we hope this study paves the way toward more durable responses and improved outcomes for patients with advanced prostate cancer.
Written by:
- Rahim Hirani, School of Medicine, New York Medical College, Valhalla, NY
- Goutam Chakraborty, Departments of Urology, Oncological Science, and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Hirani R, Nandakumar S, Zaman N, Prabhakaraalva P, King SA, Kalidindi TM, et al. BCL2 drives castration resistance in castration-sensitive prostate cancer by orchestrating reciprocal crosstalk between oncogenic pathways. Cell Rep [Internet]. 2025 Jun 24 [cited 2025 Jul 21];44(6).
- Attar RM, Takimoto CH, Gottardis MM. Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res Off J Am Assoc Cancer Res. 2009 May 15;15(10):3251–5.
- Raychaudhuri R, Lin DW, Montgomery RB. Prostate Cancer: A Review. JAMA. 2025 Apr 22;333(16):1433– 46.
- Riaz SK, Ke Y, Wang F, Kayani MA, Malik MFA. Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells. Sci Rep. 2019 Apr 29;9(1):6620.